title: Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.
abstract: The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.
authors.affiliation: Department of Veterans' Affairs Medical Center, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock 72205, USA. griffinsuet@exchange.uams.edu
authors.forename: W S
authors.initials: WS
authors.lastname: Griffin
authors.forename: J G
authors.initials: JG
authors.lastname: Sheng
authors.forename: M C
authors.initials: MC
authors.lastname: Royston
authors.forename: S M
authors.initials: SM
authors.lastname: Gentleman
authors.forename: J E
authors.initials: JE
authors.lastname: McKenzie
authors.forename: D I
authors.initials: DI
authors.lastname: Graham
authors.forename: G W
authors.initials: GW
authors.lastname: Roberts
authors.forename: R E
authors.initials: RE
authors.lastname: Mrak
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D009457:Neuroglia / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D012307:Risk Factors
chemical_list: D016207:Cytokines